Abstract
Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (β = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II–IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (β = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more—not less—depressive symptoms.
Highlights
Major depressive disorder (MDD), with a lifetime prevalence of 20%, is even more common in the context of medical illness, with a prevalence rate twice that seen in the general population[2,3,4]
Despite the prevailing psychiatric gestalt, based largely on studies examining tumor necrosis factor (TNF) antagonists[12,13,41], and contrary to our initial hypothesis, allogeneic hematopoietic stem cell transplantation (HCT) patients receiving the IL-6 antagonist tocilizumab experienced significantly worse—not better—depression, anxiety, pain, and sleep compared to HCT patients not receiving the drug
A recent report of the antidepressant effects of anti-cytokine therapies indicates a potential causative role of cytokines in depression and a potential treatment role for cytokine modulators as novel drugs for depression in chronically inflamed individuals[12]. Those treated with tocilizumab demonstrated statistically significant improvement in depressive symptoms[12]; this meta-analytic assessment was limited by several factors, including the existence of only two studies assessing the effects of tocilizumab on patient-reported outcome (PRO) measures[16,23]
Summary
Major depressive disorder (MDD), with a lifetime prevalence of 20% (ref. 1), is even more common in the context of medical illness, with a prevalence rate twice that seen in the general population[2,3,4]. Depression in the medically ill is significantly more likely to be treatment resistant[5]. Inflammation, a common feature of most medical illnesses, has been associated with specific. Recent data suggest that blocking inflammatory signaling pathways with cytokine antagonists may provide a novel treatment approach for patients with MDD10–13. This may be especially true for those with a history of treatment resistance, among those with high levels of inflammation, as occurs with medical comorbidities. Given the incomplete response of TNF blockade to treat depression[14], interleukin (IL)-6 blockade may be an effective strategy[15,16] since IL-6 is reliably elevated in MDD17–22 and associated
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